Cholesterol reduction is of great concern to patients suffering from conditions such as cardiovascular disease and atherosclerosis. Elevated cholesterol and low density lipoprotein-cholesterol (LDL-C) in particular are targets for cholesterol reduction therapy. See, for example, the guidelines of the National Cholesterol Education Program's Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults, as reported in Arch. Intern. Med. 148, 36 (1988).
Present therapeutic guidelines include the recommendation that cholesterol-lowering drugs should be considered when cholesterol and LDL-C levels remain significantly elevated after six months of appropriate dietary therapy. For example, see "National Education Program's Working Group Report on the Management of Patients with Hypertension and High Blood Cholesterol," Ann. of Intern. Med. 114, 224 (1991).
Numerous hypolipidemic agents (i.e., agents for reducing serum lipid concentration) are presently known. These include bile acid sequestrants (e.g., cholestyramine, colestipol), nicotinic acid, probucol, fibric acid derivatives (e.g., gemfibrozil, clofibrate), HMG-CoA reductase inhibitors (lovastatin, pravastatin, simvastatin) and omega-3 fatty acids found in various fish oil supplements.
However, many of the known agents have been associated with side effects that can deter or preclude their usage by many patients. Additionally, combination therapy can magnify the incidence of side effects in treated individuals. For example, cholestyramine and colestipol are associated with constipation and abdominal discomfort. Bile acid sequestrants also can reduce absorption of fat-soluble vitamins and can also interact with other drugs in the gut, rendering the drugs unabsorbable. Probucol, clofibrate and gemfibrizol can cause diarrhea, abdominal pain and nausea, and the first two agents have been associated with arrhythmias. Some bile acid sequestrants and binding resins, fibric acid derivatives, and HMG-CoA reductase inhibitors have been implicated in instances of acute hepatitis and liver damage. HMG-CoA reductase inhibitors have been associated with induced myopathy in some populations, and can also lower serum levels of ubiquinone, an essential bioenergetic component in cardiac and skeletal muscles. Niacin, especially in sustained release form, can induce chemical hepatitis. Moreover, the typically large dosages required can cause vigorous skin vasodilation or flushing, and thus adversely affect patient compliance.
Attempts have been made to provide hypolipidemic agents having fewer and/or less severe side effects. For example, U.S. Pat. No. 5,166,142 discloses the use of type IA antiarrhythmic agents, such as quinidine, procainamide or disopyramide or their pharmaceutically acceptable salts as hypolipidemic agents. U.S. Pat. No. 5,254,549 reveals the use of certain BHT ether compounds as hypolipidemic agents.
A continuing need exists for new agents which are effective in lowering serum lipids and lipoprotein fractions, such as total cholesterol, triglycerides, very low density lipoprotein cholesterol (VLDL-C) or LDL-C.